Novel Gene Therapy for Neovascular Age-Related Macular Degeneration

A novel gene therapy (ABBV-RGX-314) was well tolerated and reduced treatment burden in patients with bilateral neovascular age-related macular degeneration (AMD), according to results of a phase II study presented at the American Academy of Ophthalmology (AAO) meeting.

MedPage Today brought together three expert leaders in the field: Moderator Peter K. Kaiser, MD, of the Cleveland Clinic, is joined by Yasha S. Modi, MD, of New York University Langone Health in New York City, and Arshad M. Khanani, MD, of the University of Nevada in Reno, for a virtual roundtable discussion. This first of four exclusive episodes focuses on the ABBV-RGX-314 study.

Following is a transcript of their remarks:

Kaiser: Hi, my name is Peter Kaiser. I’m the Cheney family endowed chair in ophthalmology research at the Cole Eye Institute at the Cleveland Clinic. And I’m joined today by two of my good friends — Yasha Modi, Yasha is the assistant clinical professor at New York University Langone Health and Arshad Khanani, who’s the director of clinical research at Sierra Eye Associates. And today we’re going to do a roundtable about what we learned at the American Academy of Ophthalmology meeting in Chicago that just occurred. So welcome to the panel, gentlemen.

Modi: Thank you, all. Good to be here. Arshad, always great to see you as well.

Khanani: Yeah, thanks Peter. And looking forward to our conversations.

Kaiser: So I thought we’d start with you Arshad, because you presented really very interesting data about gene therapy. Why don’t you just tell the viewers what you presented and really why is this so important, this data?

Khanani: Thanks, Peter. So at the subspecialty day at AAO, I presented the first time results of a first time bilateral dosing study of ABBV-RGX-314 for the treatment of neovascular AMD. As you’re aware, ABBV-RGX-314 is in pivotal clinical trials for neovascular AMD. So this study was actually performed in a subset of patients where they received the subretinal gene therapy with ABBV-RGX-314 in their fellow eye. So this is the first time as a field we have performed subretinal gene therapy for neovascular AMD in both eyes for patients. As we know as clinicians, many of our patients eventually have bilateral disease, so having a durable and safe option for disease control over time is something that can be very meaningful. Obviously we know for gene therapy there are multiple parameters we need to look at, obviously efficacy, which can be different because of presence of neutralizing antibodies to the vector.

Also, in terms of safety, you want to make sure that we have a gene therapy that can be delivered safely in the fellow eye. So it was very exciting to share the data. I had data on 10 patients. These patients were previously heavily pretreated with on average around eight injections — actual injections — over the prior 12 months. They received one injection of subretinal gene therapy with ABBV-RGX-314. And the topline findings are that we did not see any new safety signals. We didn’t see any intraocular inflammation. We did see pigmentary changes in a subset of patients, which are actually something that we have seen in the prior dataset, so nothing new there. In efficacy, we were very impressed to see that 78% of patients at 9 months did not require any supplemental injection. And the two patients that did actually only needed one.

So 100% of patients either require zero or one injection. And as I said, these patients received on average eight actual injections. And in terms of treatment burden, the reduction was 97%. And then lastly, the protein production, right? We also want to see how the gene therapy is working. As you know, this gene therapy produces an anti-VEGF fab, similar to ranibizumab [Lucentis]. So looking at the protein levels in these patients, they were very similar to their first eyes that were treated. So the bottom line is very exciting news for the field for gene therapy for neovascular AMD with ABBV-RGX-314. We can actually perform treatment in both eyes without any new signals of safety and efficacy. That’s comparable to what we have seen.

Kaiser: I thought the data was really interesting in that safety was paramount, right? This is what we’re looking for in a fellow eye treatment. Yasha, with gene therapy, there are other companies looking at gene therapy, putting them in different places — suprachoroidal delivery, intravitreal delivery. Is the results that Arshad kind of just presented applicable to everybody? So in other words, is it OK to do fellow eye based on this no matter how you deliver it or how do you kind of interpret the data?

Modi: I think you have to look at each drug separately. And what we know is that different programs have had different complications and some of them being quite severe with intravitreal sort of gene therapy, having oftentimes the most severe inflammatory events. I think whenever you’re injecting gene therapy, you’re injecting so many different elements that can trigger an immune response. And so companies, physicians are working together to try and find the kind of appropriate solution. Are these ones that need topical steroid treatment? For how long? Do some of them need potentially oral steroid treatment? Do they need steroid-sparing therapy? And different programs, whether they’re doing it for something like a gene therapy in retinitis pigmentosa, may have a totally different approach than RGX-314. So I think it’s going to be variable and I think we have to think about it in each specific gene therapy that we’re delivering.

Kaiser: Yeah, I couldn’t agree more. Arshad, you’re intimately involved in all these gene therapy companies. Are the plans for these other companies — obviously Regenxbio as well as AbbVie have done this program — but have you heard, are the other companies talking about doing fellow eye studies to kind of allay some of our fears?

Khanani: I think that’s something they should do in the future, but I don’t know of any short-term plans to do that. And I completely agree with Yasha. I think subretinal gene therapy we know has been, in terms of safety, has shown the best safety profile. And part of it is because that subretinal space is immune privileged. So I don’t think we are changing the immune response because we are putting these billions of vectors, as Yasha said, in a localized space. Now of course, with intravitreal gene therapy, we’re exposing the whole eye to the vector and that is a different immune response. And as a reminder for ABBV-RGX-314, there is no steroid prophylaxis of any sort. You just give the post-op routine steroid taper as you do for a routine vitrectomy. So I think there will be differences possibly, but we don’t have that data and we will only find out once those trials have been done in the fellow eye with other modalities.

Kaiser: Super.

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